BNIP3L, also known as NIX (BCL2/adenovirus E1B interacting protein 3-like), is a mitochondrial outer membrane protein that serves as a mitophagy receptor. Mitophagy, a process maintained by BNIP3L, is crucial for eliminating dysfunctional or superfluous mitochondria via autophagy machinery, thus playing a significant role in multiple physiological and pathological processes [3].

In ischemic brains, proteasomal degradation of BNIP3L leads to mitophagy deficiency, and overexpression of wild-type BNIP3L can rescue this deficiency and protect against cerebral ischemic injury. Carfilzomib, a proteasome inhibitor, can reverse BNIP3L degradation and restore mitophagy in ischemic brains, but these effects are abolished in bnip3l-/-mice, indicating the essential role of BNIP3L in this context [1]. In glucocorticoid-induced synapse defects, glucocorticoids downregulate BNIP3L, suppressing mitophagy and leading to synaptic density and vesicle recycling reduction. Enhancing NIX can elevate mitophagy and synaptic density in corticosterone-exposed mice [2]. In addition, BNIP3L-mediated mitophagy is required for mitochondrial remodeling during the differentiation of optic nerve oligodendrocytes and cardiac progenitor cells. Abrogating BNIP3L-mediated mitophagy during differentiation leads to abnormal mitochondrial morphology and increased cell death susceptibility [4,5].

In conclusion, BNIP3L-mediated mitophagy is crucial for maintaining mitochondrial quality and quantity, playing an important role in processes such as cell differentiation and in disease conditions like cerebral ischemia, glucocorticoid-induced synapse defects. Studies using BNIP3L KO mouse models have significantly contributed to understanding its functions in these biological processes and disease areas.

References:

1. Wu, Xiaoli, Zheng, Yanrong, Liu, Mengru, Chen, Zhong, Zhang, Xiangnan. 2020. BNIP3L/NIX degradation leads to mitophagy deficiency in ischemic brains. In Autophagy, 17, 1934-1946. doi:10.1080/15548627.2020.1802089. https://pubmed.ncbi.nlm.nih.gov/32722981/

2. Choi, Gee Euhn, Lee, Hyun Jik, Chae, Chang Woo, Lim, Jae Ryong, Han, Ho Jae. 2021. BNIP3L/NIX-mediated mitophagy protects against glucocorticoid-induced synapse defects. In Nature communications, 12, 487. doi:10.1038/s41467-020-20679-y. https://pubmed.ncbi.nlm.nih.gov/33473105/

3. Li, Yue, Zheng, Wanqing, Lu, Yangyang, Chen, Zhong, Zhang, Xiangnan. 2021. BNIP3L/NIX-mediated mitophagy: molecular mechanisms and implications for human disease. In Cell death & disease, 13, 14. doi:10.1038/s41419-021-04469-y. https://pubmed.ncbi.nlm.nih.gov/34930907/

4. Yazdankhah, Meysam, Ghosh, Sayan, Shang, Peng, Zack, Donald J, Sinha, Debasish. 2021. BNIP3L-mediated mitophagy is required for mitochondrial remodeling during the differentiation of optic nerve oligodendrocytes. In Autophagy, 17, 3140-3159. doi:10.1080/15548627.2020.1871204. https://pubmed.ncbi.nlm.nih.gov/33404293/

5. Lampert, Mark A, Orogo, Amabel M, Najor, Rita H, Sussman, Mark A, Gustafsson, Åsa B. 2019. BNIP3L/NIX and FUNDC1-mediated mitophagy is required for mitochondrial network remodeling during cardiac progenitor cell differentiation. In Autophagy, 15, 1182-1198. doi:10.1080/15548627.2019.1580095. https://pubmed.ncbi.nlm.nih.gov/30741592/